Discovery of 2-[5-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-yl]-1,5,5-tri methyl-1,5-dihydro-imidazol-4-thione (BPR-890) via an active metabolite. A novel, potent and selective cannabinoid-1 receptor inverse agonist with high antiobesity efficacy in DIO mice.

Article Details

Citation Copy to clipboard

Wu CH, Hung MS, Song JS, Yeh TK, Chou MC, Chu CM, Jan JJ, Hsieh MT, Tseng SL, Chang CP, Hsieh WP, Lin Y, Yeh YN, Chung WL, Kuo CW, Lin CY, Shy HS, Chao YS, Shia KS

J Med Chem. 2009 Jul 23;52(14):4496-510. doi: 10.1021/jm900471u.

PubMed ID

19530697 [ View in PubMed

]

Abstract

By using the active metabolite 5 as an initial template, further structural modifications led to the identification of the titled compound 24 (BPR-890) as a highly potent CB1 inverse agonist possessing an excellent CB2/1 selectivity and remarkable in vivo efficacy in diet-induced obese mice with a minimum effective dose as low as 0.03 mg/kg (po qd) at the end of the 30-day chronic study. Current SAR studies along with those of many existing rimonabant-mimicking molecules imply that around the pyrazole C3-position, a rigid and deep binding pocket should exist for CB1 receptor. In addition, relative to the conventional carboxamide carbonyl, serving as a key hydrogen-bond acceptor during ligand-CB1 receptor interaction, the corresponding polarizable thione carbonyl might play a more critical role in stabilizing the Asp366-Lys192 salt bridge in the proposed CB1-receptor homology model and inducing significant selectivity for CB1R over CB2R.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Rimonabant	Cannabinoid receptor 1	IC 50 (nM)	13.2	N/A	N/A	Details
Rimonabant	Cannabinoid receptor 1	EC 50 (nM)	15.7	N/A	N/A	Details